Prodrugs of fused GABA analogs, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates generally to prodrugs of fused GABA analogs, pharmaceutical compositions of prodrugs of fused GABA analogs, methods of making prodrugs of fused GABA analogs and methods of using prodrugs of fused GABA analogs and pharmaceutical compositions of prodrugs of fused GABA analogs to treat or prevent various diseases.

[0001] This application claims the benefit under 35 U.S.C. § 119(e) fromU.S. Provisional Application Serial No. 60/432,871 filed Dec. 11, 2002,and U.S. Provisional Application Serial No. 60/433,216 filed Dec. 12,2002, which are herein incorporated by reference, in their entirety.

1. FIELD OF THE INVENTION

[0002] The present invention relates generally to prodrugs of fused GABAanalogs, pharmaceutical compositions of prodrugs of fused GABA analogs,methods of making prodrugs of fused GABA analogs and methods of usingprodrugs of fused GABA analogs and pharmaceutical compositions ofprodrugs of fused GABA analogs to treat or prevent various diseases.

2. BACKGROUND OF THE INVENTION

[0003] Gamma (“γ”)-aminobutyric acid (“GABA”) is one of the majorinhibitory transmitters in the central nervous system of mammals. GABAis not transported efficiently into the brain from the bloodstreambecause of poor transport properties that prevent passage through theblood-brain barrier. Consequently, brain cells synthesize virtually allof the GABA found in the brain (by decarboxylation of glutamic acid withpyridoxal phosphate).

[0004] GABA regulates neuronal excitability through binding to specificmembrane proteins (i.e., GABAA receptors), which results in opening ofan ion channel. The entry of chloride ion through the ion channel leadsto hyperpolarization of the recipient cell, which consequently preventstransmission of nerve impulses to other cells. Low levels of GABA havebeen observed in individuals suffering from epileptic seizures, motiondisorders (e.g., multiple sclerosis, action tremors, tardivedyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

[0005] The presence of low amounts of GABA in a number of common diseasestates has stimulated intensive interest in preparing GABA analogs,which may have superior pharmaceutical properties in comparison to GABA(e.g., the ability to cross the blood brain barrier). Accordingly, anumber of GABA analogs, with considerable International Publication No.WO 92/09560; Silverman et al., International Publication No. WO93/23383; Horwell et al., International Publication No. WO 97/29101,Horwell et al., International Publication No. WO 97/33858; Horwell etal., International Publication No. WO 97/33859; Bryans et al.,International Publication No. WO 98/17627; Guglietta et al.,International Publication No. WO 99/08671; Bryans et al., InternationalPublication No. WO 99/21824; Bryans et al., International PublicationNo. WO 99/31057; Belliotti et al., International Publication No. WO99/31074; Bryans et al., International Publication No. WO 99/31075;Bryans et al., International Publication No. WO 99/61424; Bryans et al.,International Publication No. WO 00/15611; Bryans, InternationalPublication No. WO 00/31020; Bryans et al., International PublicationNo. WO 00/50027; and Bryans et al., International Publication No. WO02/00209).

[0006] Pharmaceutically important GABA analogs include, for example,gabapentin (1), pregabalin (2), vigabatrin (3), and baclofen (4) shownabove. Gabapentin is a lipophilic GABA analog that can pass through theblood-brain barrier, which has been used to clinically treat epilepsysince 1994. Gabapentin also has potentially useful therapeutic effectsin chronic pain states (e.g., neuropathic pain, muscular and skeletalpain), psychiatric disorders (e.g., panic, anxiety, depression,alcoholism and manic behavior), movement disorders (e.g., multiplesclerosis, action tremors, tardive dyskinesia), etc. (Magnus, Epilepsia1999, 40:S66-S72).

[0007] New classes of GABA analogs, which are bicyclic amino acidderivatives have recently been described (Bryans et al., InternationalPublication No. WO 01/28978; Blakemore et al., International PublicationNo. WO 02/085839; Blakemore et al., U.S. Pat. No. 6,596,900; Blakemoreet al., International Publication No. WO 02/090318). Like other GABAanalogs, these compounds are useful medicaments for the treatment orprevention of epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain, inflammatory disease, insomnia, gastrointestinal disordersand ethanol withdrawal syndrome.

[0008] Rapid systemic clearance and/or poor oral bioavailability aresignificant problems with many GABA analogs such as gabapentin, whichconsequently require frequent dosing to maintain a therapeutic orprophylactic concentration in the systemic circulation (Bryans et al.,Med. Res. Rev. 1999, 19, 149-177). For example, dosing regimens of300-600 mg doses of gabapentin administered three times per day aretypically used for anticonvulsive therapy. Higher doses (1800-3600 mg/din divided doses) are typically used for the treatment of neuropathicpain states.

[0009] Sustained released formulations are a conventional solution tothe problem of rapid systemic clearance, as is well known to those ofskill in the art (See, e.g., “Remington's Pharmaceutical Sciences,”Philadelphia College of Pharmacy and Science, 19th Edition, 1995).Osmotic delivery systems are also recognized methods for sustained drugdelivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm. 2000,26:695-708). Many GABA analogs are not absorbed via the large intestinebut rather are typically absorbed in the small intestine by the largeneutral amino acid transporter (“LNAA”) (Jezyk et al., Pharm. Res. 1999,16, 519-526). The rapid passage of conventional dosage forms through theproximal absorptive region of the gastrointestinal tract has preventedthe successful application of sustained release technologies to manyGABA analogs.

[0010] Thus, there is a significant need for more readily orallyabsorbable versions of GABA analogs and effective sustained releaseversions of GABA analogs to minimize increased dosing frequency due torapid systemic clearance, particularly of fused GABA analogs.

3. SUMMARY OF THE INVENTION

[0011] The present invention satisfies these and other needs byproviding prodrugs of fused GABA analogs, pharmaceutical compositions ofprodrugs of fused GABA analogs, methods of making prodrugs of fused GABAanalogs and methods of using prodrugs of fused GABA analogs andpharmaceutical compositions of prodrugs of fused GABA analogs to treator prevent various diseases.

[0012] In a first aspect, the present invention provides compounds ofstructural formula (I):

[0013] or a pharmaceutically acceptable salt, hydrate, solvate orN-oxide thereof, wherein:

[0014] n is 1, 2, 3, 4, 5 or 6;

[0015] o is 0, 1, 2 or 3;

[0016] p is 0, 1 or 2;

[0017] r is 0 or 1;

[0018] R¹ and R³ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

[0019] R² is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, acylamino, substituted acylamino,alkylamino, substituted alkylamino, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, oxycarbonyl or substituted oxycarbonyl, oroptionally, R² and R³ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0020] R⁴ and R⁵ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, oxycarbonyl or substitutedoxycarbonyl or optionally, R⁴ and R⁵ together with the carbon atom towhich they are bonded form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0021] R⁶ is acyl, substituted acyl, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

[0022] each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

[0023] In a second aspect, the present invention provides pharmaceuticalcompositions, which generally comprise one or more compounds of theinvention, pharmaceutically acceptable salts, hydrates, solvates orN-oxides thereof and a pharmaceutically acceptable vehicle such as adiluent, carrier, excipient or adjuvant. The choice of diluent, carrier,excipient and adjuvant will depend upon, among other factors, thedesired mode of administration.

[0024] In a third aspect, the present invention provides methods fortreating or preventing various diseases or disorders. The methodsgenerally involve administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compound and/orpharmaceutical composition of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

[0025] “Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0026] The term “alkyl” is specifically intended to include groupshaving any degree or level of saturation, i.e., groups havingexclusively single carbon-carbon bonds, groups having one or more doublecarbon-carbon bonds, groups having one or more triple carbon-carbonbonds and groups having mixtures of single, double and triplecarbon-carbon bonds. Where a specific level of saturation is intended,the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.Preferably, an alkyl group comprises from 1 to 20 carbon atoms, morepreferably, from 1 to 10 carbon atoms, even more preferably, from 1 to 6carbon atoms.

[0027] “Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

[0028] “Alkenyl” by itself or as part of another substituent refers toan unsaturated branched, straight-chain or cyclic alkyl radical havingat least one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

[0029] “Alkynyl” by itself or as part of another substituent refers toan unsaturated branched, straight-chain or cyclic alkyl radical havingat least one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl,-but-3-yn-1-yl, etc.; and the like.

[0030] “Acyl” by itself or as part of another substituent refers to aradical —C(O)R³⁰, where R³⁰ is hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

[0031] “Alkylamino” by itself or as part of another substituent refersto a radical —NHR³¹ where R³¹ represents an alkyl or cycloalkyl group asdefined herein. Representative examples include, but are not limited to,methylamino, ethylamino, 1-methylethylamino, cyclohexyl amino and thelike.

[0032] “Alkoxy” by itself or as part of another substituent refers to aradical —OR³² where R³² represents an alkyl or cycloalkyl group asdefined herein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

[0033] “Alkoxycarbonyl” by itself or as part of another substituentrefers to a radical —C(O)OR³² where R³² represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, cyclohexyloxycarbonyl and the like.

[0034] “Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Typical aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene and the like. Preferably, an aryl groupcomprises from 6 to 20 carbon atoms, more preferably from 6 to 12 carbonatoms.

[0035] “Arylalkyl” by itself or as part of another substituent refers toan acyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is (C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), more preferably, anarylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) and the aryl moiety is(C₆-C₁₂).

[0036] “Carbamoyl” by itself or as part of another substituent refers tothe radical —C(O)N(R³³)R³⁴ where R³³ and R³⁴ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl orsubstituted heteroaryl, as defined herein.

[0037] “Compounds of the invention” refers to compounds encompassed bythe generic formulae disclosed herein and includes any specificcompounds within those formulae whose structure is disclosed herein. Thecompounds of the invention may be identified either by their chemicalstructure and/or chemical name. When the chemical structure and chemicalname conflict, the chemical structure is determinative of the identityof the compound. The compounds of the invention may contain one or morechiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers or diastereomers. Accordingly, when stereochemistry atchiral centers is not specified, the chemical structures depicted hereinencompass all possible configurations at those chiral centers includingthe stereoisomerically pure form (e.g., geometrically pure,enantiomerically pure or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can beresolved into their component enantiomers or stereoisomers usingseparation techniques or chiral synthesis techniques well known to theskilled artisan. The compounds of the invention may also exist inseveral tautomeric forms including the enol form, the keto form andmixtures thereof. Accordingly, the chemical structures depicted hereinencompass all possible tautomeric forms of the illustrated compounds.The compounds of the invention also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds of the invention include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O and ¹⁷O. Compounds of theinvention may exist in unsolvated forms as well as solvated forms,including hydrated forms and as N-oxides. In general, the hydrated,solvated and N-oxide forms are within the scope of the presentinvention. Certain compounds of the present invention may exist inmultiple crystalline or amorphous forms. In general, all physical formsare equivalent for the uses contemplated by the present invention andare intended to be within the scope of the present invention. Further,it should be understood, when partial structures of the compounds of theinvention are illustrated, that brackets indicate the point ofattachment of the partial structure to the rest of the molecule.

[0038] “Cycloalkyl” by itself or as part of another substituent refersto a saturated or unsaturated cyclic alkyl radical. Where a specificlevel of saturation is intended, the nomenclature “cycloalkanyl” or“cycloalkenyl” is used. Typical cycloalkyl groups include, but are notlimited to, groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane and the like. Preferably, the cycloalkyl group is (C₃-C₁₀)cycloalkyl, more preferably (C₃-C₇) cycloalkyl.

[0039] “Cycloheteroalkyl” by itself or as part of another substituentrefers to a saturated or unsaturated cyclic alkyl radical in which oneor more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom. Typicalheteroatoms to replace the carbon atom(s) include, but are not limitedto, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, azirines, thiiranes, imidazolidine,morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,quinuclidine and the like.

[0040] “Derived from a fused GABA analog” refers to a moiety that isstructurally related to a fused GABA analog. The structure of the moietyis identical to the compound except at 1 or 2 positions. At thesepositions, a hydrogen atom attached to the amino group, and (optionally)the hydroxyl moiety of the carboxylic acid group has been replaced witha covalent bond that serves as a point of attachment to another moiety.

[0041] “Dialkylamino” by itself or as part of another substituent refersa radical —NR³⁵R³⁶ where R³⁵ and R³⁶ are independently an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, dimethylamino, methylethylamino,di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like.

[0042] “Fused GABA analog” refers to a compound, unless specifiedotherwise, as having the following structure:

[0043] wherein:

[0044] n is 1, 2, 3, 4, 5 or 6;

[0045] o is 0, 1, 2 or 3;

[0046] p is 0, 1 or 2; and

[0047] each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independentlyhydrogen, alkyl substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

[0048] “Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl” bythemselves or as part of another substituent refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatomic groups. Typicalheteroatomic groups which can be included in these groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR³⁷R³⁸—, ═N—N═,—N═N—, —N═N—NR³⁹R⁴⁰, —PR⁴¹—, —P(O)₂—, —POR⁴²—, —O—P(O)₂—, —SO—, —SO₂—,—SnR⁴³R⁴⁴— and the like, where R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

[0049] “Heteroaryl” by itself or as part of another substituent refersto a monovalent heteroaromatic radical derived by the removal of onehydrogen atom from a single atom of a parent heteroaromatic ring system.Typical heteroaryl groups include, but are not limited to, groupsderived from acridine, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. Preferably, the heteroaryl group isfrom 5-20 membered heteroaryl, more preferably from 5-10 memberedheteroaryl. Preferred heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

[0050] “Heteroarylalkyl” by itself or as part of another substituentrefers to an acyclic alkyl radical in which one of the hydrogen atomsbonded to a carbon atom, typically a terminal or sp³ carbon atom, isreplaced with a heteroaryl group. Where specific alkyl moieties areintended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/orheterorylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is 1-10 membered and theheteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moietyof the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a5-12-membered heteroaryl.

[0051] “Oxycarbonyl” by itself or as part of another substituent refersto a radical —C(O)—OR⁴⁵ where R⁴⁵ represents an alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroarylsubstituted heteroaryl, heteroarylalkyl or substituted heteroarylalkylgroup as defined herein. Representative examples include, but are notlimited to, methoxycarbonyl, piperdineoxycarbonyl, phenyloxycarbonyl,benzyloxycarbonyl and the like.

[0052] “Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

[0053] “Parent Heteroaromatic Ring System” refers to a parent aromaticring system in which one or more carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Typical heteroatoms to replace the carbon atoms include, butare not limited to, N, P, O, S, Si, etc. Specifically included withinthe definition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated or unsaturated, such as, for example,arsindole, benzodioxan, benzofuran, chromane, chromene, indole,indoline, xanthene, etc. Typical parent heteroaromatic ring systemsinclude, but are not limited to, arsindole, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

[0054] “Pharmaceutical composition” refers to at least one compound ofthe invention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient.

[0055] “Pharmaceutically acceptable salt” refers to a salt of a compoundof the invention, which possesses the desired pharmacological activityof the parent compound. Such salts include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like; or (2) salts formed when an acidic proton present in theparent compound is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine and the like.

[0056] “Pharmaceutically acceptable vehicle” refers to a diluent,adjuvant, excipient or carrier with which a compound of the invention isadministered.

[0057] “Patient” includes humans. The terms “human” and “patient” areused interchangeably herein.

[0058] “Preventing” or “prevention” refers to a reduction in risk ofacquiring a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a patient that may beexposed to or predisposed to the disease but does not yet experience ordisplay symptoms of the disease).

[0059] “Prodrug” refers to a derivative of a drug molecule that requiresa transformation within the body to release the active drug. Prodrugsare frequently, although not necessarily, pharmacologically inactiveuntil converted to the parent drug. A hydroxyl containing drug may beconverted to, for example, to a sulfonate, ester or carbonate prodrug,which may be hydrolyzed in vivo to provide the hydroxyl compound. Anamino containing drug may be converted, for example, to a carbamate,amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug,which may be hydrolyzed in vivo to provide the amino compound. Acarboxylic acid drug may be converted to an ester (including silylesters and thioesters), amide or hydrazide prodrug, which be hydrolyzedin vivo to provide the carboxylic acid compound. Prodrugs for drugswhich functional groups different than those listed above are well knownto the skilled artisan.

[0060] “Promoiety” refers to a form of protecting group that when usedto mask a functional group within a drug molecule converts the drug intoa prodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

[0061] “Protecting group” refers to a grouping of atoms that whenattached to a reactive functional group in a molecule masks, reduces orprevents reactivity of the functional group. Examples of protectinggroups can be found in Green et al., “Protective Groups in OrganicChemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison et al., “Compendium ofSynthetic Organic Methods”, Vols. 1-8 (John Wiley and Sons, 1971-1996).Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyprotecting groups include, but are not limited to, those where thehydroxy group is either acylated or alkylated such as benzyl, and tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers and allyl ethers.

[0062] “Substituted” refers to a group in which one or more hydrogenatoms are independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,-M, —R⁶⁰, —O⁻, ═O, —OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN,—OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁶⁰,—OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹),—C(O)R⁶⁰, —C(S)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹,—C(O)O⁻, —C(S)OR⁶⁰,—NR⁶²C(O)NR⁶⁰R⁶¹, —NR⁶²C(S)NR⁶OR⁶¹, —NR⁶²C(NR⁶³)NR⁶⁰R⁶¹ and—C(NR⁶²)NR⁶⁰R⁶¹ where M is independently a halogen; R⁶⁰, R⁶¹, R⁶² andR⁶³ are independently hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl, or optionally R⁶⁰ and R⁶¹ togetherwith the nitrogen atom to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring; and R⁶⁴ and R⁶⁵ are independentlyhydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl, or optionallyR⁶⁴ and R⁶⁵ together with the nitrogen atom to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.Preferably, substituents include -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —S⁻, ═S,—NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R⁶⁰,—OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹),—C(O)R⁶⁰, —C(S)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹,—C(O)O⁻, —NR⁶²C(O)NR⁶⁰R⁶¹,more preferably, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂,—S(O)₂R⁶⁰, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰,—C(O)NR⁶⁰R⁶¹,—C(O)O⁻, most preferably, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰,—NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂, —S(O)₂R⁶⁰, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰,—C(O)OR⁶⁰ ,—C(O)O⁻, where R⁶⁰, R⁶¹ and R⁶² are as defined above.

[0063] “Treating” or “treatment” of any disease or disorder refers, inone embodiment, to ameliorating the disease or disorder (i.e., arrestingor reducing the development of the disease or at least one of theclinical symptoms thereof). In another embodiment “treating” or“treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the patient. In yet another embodiment,“treating” or “treatment” refers to inhibiting the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

[0064] “Therapeutically effective amount” means the amount of a compoundthat, when administered to a patient for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the patientto be treated.

4.2 Compounds of the Invention

[0065] In a first embodiment, the present invention provides compoundsof structural Formula (I):

[0066] or a pharmaceutically acceptable salt, hydrate, solvate orN-oxide thereof, wherein:

[0067] n is 1, 2, 3, 4, 5 or 6;

[0068] o is 0, 1, 2 or 3;

[0069] p is 0, 1 or 2;

[0070] r is 0 or 1;

[0071] R¹ and R³ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

[0072] R² is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, acylamino, substituted acylamino,alkylamino, substituted alkylamino, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, oxycarbonyl or substituted oxycarbonyl, oroptionally, R² and R³ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0073] R⁴ and R⁵ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, oxycarbonyl or substitutedoxycarbonyl or optionally, R⁴ and R⁵ together with the carbon atom towhich they are bonded form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0074] R⁶ is acyl, substituted acyl, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

[0075] each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

[0076] In a second embodiment, the present invention provides a compoundhaving structural Formula (II):

[0077] In a third embodiment, the present invention provides a compoundhaving structural Formula (III):

[0078] wherein each of R¹¹ and R¹² is independently hydrogen or methyl.

[0079] In a fourth embodiment, the present invention provides compoundsof structural formula (III) derived from fused GABA analogs selectedfrom the group consisting of(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, (1α, 3α, 5α)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, (1α, 5β)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, (1α, 3β, 5α)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid, ((1R,5S)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid and((1S, 5R)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-aceticacid.

[0080] In a fifth embodiment, the present invention provides compoundshaving structural Formula (IV):

[0081] wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ isindependently hydrogen or methyl.

[0082] In a sixth embodiment, the present invention provides compoundsof structural Formula (IV) derived from fused GABA analogs selected fromthe group consisting of (3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (1α, 3α, 5α) (3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,(1α, 5β) (3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (1α, 3β,5α) (3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, ((1R,5S)-3-Aminomethyl-1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,((1S, 5R)-3-Aminomethyl-1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, cis-((1S, 2R, 4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,trans-((1S, 2R, 4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,((1S, 5R, 6S,7R)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid and((1S, 5R, 6R,7S)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid.

[0083] In a seventh embodiment, the present invention provides compoundshaving structural Formula (V):

[0084] In a eighth embodiment, the present invention provides compoundsof structural Formula (V) derived from fused GABA analogs selected fromthe group consisting of (2-Aminomethyl-octahydro-pentalen-2-yl)-aceticacid, (1α, 3α, 5α) (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,(1α, 5β) (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid and (1α,3β, 5α) (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid.

[0085] In a ninth embodiment, the present invention provides compoundshaving structural Formula (VI):

[0086] In a tenth embodiment, the present invention provides compoundsof structural Formula (VI) derived from fused GABA analogs selected fromthe group consisting of (2-Aminomethyl-octahydro-inden-2-yl)-aceticacid, (1αc, 6α, 8α) (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,(1α, 6β) (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid and (1α, 6α,8β) (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid.

[0087] In a eleventh embodiment, the present invention providescompounds having structural Formula (VII):

[0088] wherein R¹¹ and R¹² are independently hydrogen or methyl.

[0089] In a twelfth embodiment, the present invention provides compoundsof structural Formula (VII) derived from fused GABA analogs selectedfrom the group consisting of(2-Aminomethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid, ((1S, 2S,5R)-2-Aminomethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid, ((1R, 2S,5S)-2-Aminomethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid, ((1S, 2R,5R)-2-Aminomethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid, ((1R, 2R,5S)-2-Aminomethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid,(2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid, ((1S,2S, 5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid,((1R, 2S, 5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-aceticacid, ((1S, 2R,5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-acetic acid and((1R, 2R, 5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-aceticacid.

[0090] In a thirteenth embodiment, the present invention providescompounds having structural Formula (VIII):

[0091] In a fourteenth embodiment, the present invention providescompounds of structural Formula (VIII) derived from fused GABA analogsselected from the group consisting of(6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((1R, 5R,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((1S, 5S,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((1R, 5R,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid and ((1S, 5S,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid.

[0092] In a fifteenth embodiment, the present invention providescompounds having structural Formula (IX):

[0093] In a sixteenth embodiment, the present invention providescompounds of structural Formula (IX) derived from fused GABA analogsselected from the group consisting of(7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((1R, 6R,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((1S, 6S,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((1R, 6R,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid and ((1S, 6S,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid.

[0094] In a seventeenth embodiment, the present invention providescompounds of structural Formula (X):

[0095] In a eighteenth embodiment, the present invention providescompounds of structural Formula (X) derived from fused GABA analogsselected from the group consisting of (1R, 7R,8S)-8-aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid, ((1S, 7S,8S)-8-aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid, ((1R, 7R,8R)-8-aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid and ((1S, 7S,8R)-8-aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid.

[0096] Preferably, in the above embodiments, R¹ is hydrogen.Alternatively, R¹ may be hydrogen, alkanyl, substituted alkanyl,alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl orsubstituted arylalkyl. Preferably, R¹ is hydrogen, methyl, ethyl,benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

[0097] Preferably, in the eighteen embodiments above, R² is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkyl or substitutedheteroarylalkanyl. More preferably, R² is hydrogen, alkanyl orcycloalkanyl. Even more preferably, R² is selected from the groupconsisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl and cyclohexyl.

[0098] Preferably, in the first eighteen embodiments above, R² isselected from the group consisting of substituted alkanyl. Morepreferably, R² is selected from the group consisting of —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ and —CH₂CH₂CH₂NHC(NH)NH₂.

[0099] Preferably, in the first eighteen embodiments above, R² isselected from the group consisting of aryl, arylalkanyl, substitutedarylalkanyl and heteroarylalkanyl. More preferably, R² is selected fromthe group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl,4-imidazolylmethyl and 3-indolylmethyl.

[0100] Preferably, in the first eighteen embodiments above, R² and R³together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. More preferably, R² and R³together with the atoms to which they are bonded form an azetidine,pyrrolidine or piperidine ring. Preferably, in the first eighteenembodiments above, R³ is hydrogen, alkyl, substituted alkyl, arylalkylor substituted arylalkyl. More preferably, R³ is hydrogen, methyl, ethylor benzyl.

[0101] Preferably, in the first eighteen embodiments above, R⁴ and R⁵are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl or substituted heteroaryl. Morepreferably, R⁴ and R⁵ are independently hydrogen, alkyl, alkoxycarbonyl,aryl, arylalkyl or heteroaryl. Most preferably, R⁴ and R⁵ areindependently hydrogen, methyl, ethyl, propyl, isopropyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl,3-pyridyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl.

[0102] Preferably, in the first eighteen embodiments above, R⁶ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,heteroaryl or substituted heteroaryl. More preferably, R⁶ is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

[0103] Preferably, in the first embodiment above, each of R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independently hydrogen, alkyl orsubstituted alkyl. More preferably, each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³ and R¹⁴ is independently hydrogen or methyl.

[0104] Preferably, in the first eighteen embodiments above, R¹ ishydrogen and R² and R³ together with the atoms to which they areattached form a pyrrolidine ring. Preferably, in this embodiment, R¹ ishydrogen. Alternatively, R¹ is methyl, ethyl, benzyl, —C(CH₃)═CH₂,—CH₂C(O)N(CH₃)₂,

[0105] Preferably, in the first eighteen embodiments above, R³ ishydrogen and R² is selected from the group consisting of hydrogen,methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl,4-imidazolylmethyl, 3CH₂OH, CH(OH)CH₃, -CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ and—CH₂CH₂CH₂NHC(NH)NH₂. Preferably, in this embodiment, R¹ is hydrogen.Alternatively, R¹ is methyl, ethyl, benzyl, —C(CH₃)═CH₂,—CH₂C(O)N(CH₃)₂,

[0106] Preferably, in the first eighteen embodiments above, R¹ ishydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl,aryl, substituted aryl, arylalkyl or substituted arylalkyl, R² ishydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl orsubstituted heteroarylalkanyl or optionally R² and R³ together with theatoms to which they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring, R³ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl, R⁴ and R⁵ are independentlyhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl or substituted heteroaryl and R⁶ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,heteroaryl or substituted heteroaryl.

[0107] Preferably, in the first eighteen embodiments above, r is 0, R⁴is methyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0108] Preferably, in the first eighteen embodiments above, r is 0, R⁴is ethyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0109] Preferably, in the first eighteen embodiments above, r is 0, R⁴is propyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0110] Preferably, in the first eighteen embodiments above, r is 0, R⁴is isopropyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0111] Preferably, in the first eighteen embodiments above, r is 0, R⁴is butyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl;cyclopentyl, cyclohexyl and 3-pyridyl.

[0112] Preferably, in the first eighteen embodiments above, r is 0, R⁴is isobutyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0113] Preferably, in the first eighteen embodiments above, r is 0, R⁴is sec-butyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0114] Preferably, in the first eighteen embodiments above, r is 0, R⁴is tert-butyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-diethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0115] Preferably, in the first eighteen-embodiments above, r is 0, R⁴is cyclopentyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0116] Preferably, in the first eighteen embodiments above, r is 0, R⁴is cyclohexyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0117] Preferably, in the first eighteen embodiments above, r is 0, R⁴is phenyl, R¹and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0118] Preferably, in the first eighteen embodiments above, r is 0, R⁴is benzyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0119] Preferably, in the first eighteen embodiments above, r is 0, R⁴is phenethyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0120] Preferably, in the first eighteen embodiments above, r is 0, R⁴is 3-pyridyl, R¹ and R⁵ are hydrogen and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0121] Preferably, in the first eighteen embodiments above, r is 0, R⁴is methyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0122] Preferably, in the first eighteen embodiments above, r is 0, R⁴is methoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0123] Preferably, in the first eighteen embodiments above, r is 0, R⁴is ethoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0124] Preferably, in the first eighteen embodiments above, r is 0, R³is propoxycarbonyl, R⁴ is methyl, R¹ is hydrogen and R⁶ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0125] Preferably, in the first eighteen embodiments above, r is 0, R⁴is isopropoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0126] Preferably, in the first eighteen embodiments above, r is 0, R⁴is butoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0127] Preferably, in the first eighteen embodiments above, r is 0, R⁴is isobutoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0128] Preferably, in the first eighteen embodiments above, r is 0, R⁴is sec-butoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0129] Preferably, in the first eighteen embodiments above, r is 0, R⁴is tert-butoxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0130] Preferably, in the first eighteen embodiments above, r is 0, R⁴is cyclohexyloxycarbonyl, R⁵ is methyl, R¹ is hydrogen and R⁶ isselected from the group consisting of methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0131] Preferably, in the first eighteen embodiments above, r is 0, eachof R¹, R⁴ and R⁵ is hydrogen, and R⁶ is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 3-pyridyl.

[0132] Preferably, in the first eighteen embodiments above, R³ ishydrogen, and R² is selected from the group consisting of hydrogen,methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl,4-imidazolylmethyl, 3-indolylmethyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂and —CH₂CH₂CH₂NHC(NH)NH₂.

4.3 Synthesis of the Compounds of the Invention

[0133] Those of skill in the art will appreciate that a preferredsynthetic route to the compounds of the invention will consist ofattaching promoieties to fused GABA analogs. Methods have been describedin the art for the synthesis of fused GABA analogs (Blakemore et al.,International Publication No. WO 02/085839; Blakemore et al.,International Publication No. WO 02/090318; and Bryans et al.,International Publication No. WO 01/28978). Other methods will beapparent to the skilled artisan for synthesizing fused GABA analogs inview of the references provided above. The promoieties described herein,are known in the art and may be prepared and attached to fused GABAanalogs by established procedures (See e.g., Green et al., “ProtectiveGroups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991); Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996; Larock “Comprehensive Organic Transformations,” VCHPublishers, 1989; and Paquette, “Encyclopedia of Reagents for OrganicSynthesis,” John Wiley & Sons, 1995). Preferably, the promoietiesillustrated herein, may be attached to fused GABA analogs by theprocedures described in Cundy et al., U.S. patent application Ser. No.10/710,127; Gallop et al., U.S. patent application Ser. No. 10/171,485;and Gallop et al., U.S. patent application Ser. No. 10/167,197.

4.4 Therapeutic Uses

[0134] In accordance with the invention, a compound and/orpharmaceutical composition of the invention is administered to apatient, preferably a human, suffering from epilepsy, depression,anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially, neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders, hot flashes, restless legssyndrome, urinary incontinence or ethanol withdrawal syndrome. Further,in certain embodiments, the compounds and/or pharmaceutical compositionsof the invention are administered to a patient, preferably a human, as apreventative measure against various diseases or disorders. Thus, thecompounds and/or pharmaceutical compositions of the invention may beadministered as a preventative measure to a patient having apredisposition for epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially, neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders, hot flashes, restless legs syndrome, urinaryincontinence and ethanol withdrawal syndrome. Accordingly, the compoundsand/or pharmaceutical compositions of the invention may be used for theprevention of one disease or disorder and concurrently treating another(e.g., prevention of psychosis while treating gastrointestinaldisorders; prevention of neuropathic pain while treating ethanolwithdrawal syndrome).

[0135] The suitability of the compounds and/or pharmaceuticalcompositions of the invention in treating or preventing epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes,restless legs syndrome, urinary incontinence and ethanol withdrawalsyndrome may be determined by methods described in the art (See, e.g.,Satzinger et al., U.S. Pat. No. 4,024,175; Satzinger et al., U.S. Pat.No. 4,087,544; Woodruff, U.S. Pat. No. 5,084,169; Silverman et al., U.S.Pat. No. 5,563,175; Singh, U.S. Pat. No. 6,001,876; Horwell et al., U.S.Pat. No. 6,020,370; Silverman et al., U.S. Pat. No.6,028,214; Horwell etal., U.S. Pat. No.6,103,932; Silverman et al., U.S. Pat. No. 6,117,906;Silverman, International Publication No. WO 92/09560; Silverman et al.,International Publication No. WO 93/23383; Horwell et al., InternationalPublication No. WO 97/29101, Horwell et al., International PublicationNo. WO 97/33858; Horwell et al., International Publication No. WO97/33859; Bryans et al., International Publication No. WO 98/17627;Guglietta et al., International Publication No. WO 99/08671; Bryans etal., International Publication No. WO 99/21824; Bryans et al.,International Publication No. WO 99/31057; Magnus-Miller et al.,International Publication No. WO 99/37296; Bryans et al., InternationalPublication No. WO 99/31075; Bryans et al., International PublicationNo. WO 99/61424; Pande, International Publication No. WO 00/23067;Bryans, International Publication No. WO 00/31020; Bryans et al.,International Publication No. WO 00/50027; Bryans et al, InternationalPublication No. WO 02/00209; Bryans et al., International PublicationNo. WO 01/28978 and Blakemore et al., International Publication No. WO02/085839).

[0136] Accordingly, it is well with the capability of those of skill inthe art to assay and use the compounds of the invention and/orpharmaceutical compositions thereof to treat or prevent the abovediseases or disorders.

4.5 Therapeutic/Prophylactic Administration

[0137] The compounds and/or pharmaceutical compositions of the inventionmay be advantageously used in human medicine. As previously described inSection 4.4 above, compounds and/or pharmaceutical compositions of theinvention are useful for the treatment or prevention of epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especially,neuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), arthritis, insomnia, gastrointestinal disorders, hotflashes, restless legs syndrome, urinary incontinence, insomnia,gastrointestinal disorders or ethanol withdrawal syndrome.

[0138] When used to treat or prevent the above disease or disorderscompounds and/or pharmaceutical compositions of the invention may beadministered or applied singly, in combination with other agents. Thecompounds and/or pharmaceutical compositions of the invention may alsobe administered or applied singly, in combination with otherpharmaceutically active agents, including other compounds and/orpharmaceutical compositions of the invention.

[0139] The current invention provides methods of treatment andprophylaxis by administration to a patient of a therapeuticallyeffective amount of a pharmaceutical composition or compound of theinvention. The patient may be an animal, is more preferably a mammal,and most preferably a human.

[0140] The present compounds and/or pharmaceutical compositions of theinvention, which comprise one or more compounds of the invention, arepreferably administered orally. The compounds and/or pharmaceuticalcompositions of the invention may also be administered by any otherconvenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.). Administration can besystemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer a compound and/or composition ofthe invention. Methods of administration include, but are not limitedto, intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intranasal,intracerebral, intravaginal, transdermal, rectally, by inhalation, ortopically, particularly to the ears, nose, eyes, or skin.

[0141] In particularly preferred embodiments, the compounds and/orpharmaceutical compositions of the invention can be delivered viasustained release systems, preferably oral sustained release systems. Inone embodiment, a pump may be used (Langer, supra; Sefton, 1987, CRCCrit Ref Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J Med.321:574).

[0142] In another embodiment polymeric materials can be used (see“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Langeret al., 1983, J Macromol. Sci. Rev. Macromol Chem.23:61; Levy et al., 1985, Science 228: 190; During et al., 1989, Ann.Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In apreferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

[0143] In another embodiment, enteric-coated preparations can be usedfor oral sustained release administration. Preferred coating materialsinclude polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

[0144] In still another embodiment, osmotic delivery systems are usedfor oral sustained release administration (Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708). In a preferred embodiment, OROS™ osmoticdevices are used for oral sustained release delivery devices (Theeuweset al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No.3,916,899).

[0145] In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compounds and/or pharmaceuticalcompositions of the invention, thus requiring only a fraction of thesystemic dose (See, e.g., Goodson, in “Medical Applications ofControlled Release,” supra, vol. 2, pp. 115-138 (1984)). Othercontrolled-release systems discussed in Langer, 1990, Science249:1527-1533 may also be used.

[0146] The compounds and/or pharmaceutical compositions of the inventionpreferably provide fused GABA analogs upon in vivo administration to apatient. While not wishing to bound by theory, the promoiety orpromoieties of the compounds and/or pharmaceutical compositions of theinvention may be cleaved either chemically and/or enzymatically. One ormore enzymes present in the stomach, intestinal lumen, intestinaltissue, blood, liver, brain or any other suitable tissue of a mammal mayenzymatically cleave the promoiety or promoieties of the compoundsand/or compositions of the invention. The mechanism of cleavage is notimportant to the current invention.

[0147] While not wishing to bound by theory, the promoiety orpromoieties of the compounds and/or pharmaceutical compositions of theinvention may be cleaved prior to absorption by the gastrointestinaltract (e.g., within the stomach or intestinal lumen) and/or afterabsorption by the gastrointestinal tract (e.g., in intestinal tissue,blood, liver or other suitable tissue of a mammal). If the promoiety orpromoieties of the compounds of the invention are cleaved prior toabsorption by the gastrointestinal tract, the resulting fused GABAanalogs may be absorbed into the systemic circulation conventionally(e.g. via amino acid transporter(s) located in the small intestine). Ifthe promoiety or promoieties of the compounds of the invention arecleaved after absorption by the gastrointestinal tract, these fused GABAanalog prodrugs may have the opportunity to be absorbed into thesystemic circulation either by passive diffusion, active transport or byboth passive and active processes.

[0148] If the promoiety or promoieties of the compounds of the inventionare cleaved after absorption by the gastrointestinal tract, these fusedGABA analog prodrugs may have the opportunity to be absorbed into thesystemic circulation from the large intestine. In this situation, thecompounds and/or pharmaceutical compositions of the invention arepreferably administered as sustained release systems. In a preferredembodiment, the compounds and/or pharmaceutical compositions of theinvention are delivered by oral sustained release administration.Preferably, in this embodiment, the compounds and/or pharmaceuticalcompositions of the invention are administered twice per day (morepreferably, once per day).

4.6 Pharmaceutical Compositions

[0149] The present pharmaceutical compositions contain a therapeuticallyeffective amount of one or more compounds of the invention, preferably,in purified form, together with a suitable amount of a pharmaceuticallyacceptable vehicle, to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris a preferred vehicle when a compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present pharmaceutical compositions, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents may be used.

[0150] Pharmaceutical compositions comprising a compound of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the inventioninto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

[0151] The present compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the pharmaceuticallyacceptable vehicle is a capsule (e.g., Grosswald et al., U.S. Pat. No.5,698,155). Other examples of suitable pharmaceutical vehicles have beendescribed in the art (see, Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995).Preferred compositions of the invention are formulated for oraldelivery, particularly for oral sustained release administration.

[0152] Pharmaceutical compositions for oral delivery may be in the formof tablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered pharmaceutical compositions may contain one or moreoptional agents, for example, sweetening agents such as fructose,aspartame or saccharin, flavoring agents such as peppermint, oil ofwintergreen, or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, where in tablet orpill form, the pharmaceutical compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andpharmaceutical compositions of the invention. In these later platforms,fluid from the environment surrounding the capsule is imbibed by thedriving compound, which swells to displace the agent or agentcomposition through an aperture. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations. A time delay material suchas glycerol monostearate or glycerol stearate may also be used. Oralcompositions can include standard vehicles such as mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate, etc. Such vehicles are preferably of pharmaceutical grade.

[0153] For oral liquid preparations such as, for example, suspensions,elixirs and solutions, suitable carriers, excipients or diluents includewater, saline, alkyleneglycols (e.g., propylene glycol), polyalkyleneglycols (e.g., polyethylene glycol) oils, alcohols, slightly acidicbuffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate atbetween about 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

[0154] Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see,e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No.5,556,61 1). A compound of the invention may also be formulated inrectal or vaginal compositions such as suppositories or retentionenemas, e.g., containing conventional suppository bases such as cocoabutter or other glycerides. In addition to the formulations describedpreviously, a compound of the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, a compound of the inventionmay be formulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

[0155] When a compound of the invention is acidic, it may be included inany of the above-described formulations as the free acid, apharmaceutically acceptable salt, a solvate or hydrate. Pharmaceuticallyacceptable salts substantially retain the activity of the free acid, maybe prepared by reaction with bases and tend to be more soluble inaqueous and other protic solvents than the corresponding free acid form.

4.7 Therapeutic Doses

[0156] A compound of the invention and/or pharmaceutical compositionsthereof, will generally be used in an amount effective to achieve theintended purpose. For use to treat or prevent diseases or disorders suchas epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders, hot flashes, restless legs syndrome, urinary incontinence orethanol withdrawal syndrome, the compounds of the invention and/orpharmaceutical compositions thereof, are administered or applied in atherapeutically effective amount.

[0157] The amount of a compound of the invention and/or pharmaceuticalcomposition thereof that will be effective in the treatment of aparticular disorder or condition disclosed herein will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques known in the art. In addition, in vitro or in vivoassays may optionally be employed to help identify optimal dosageranges. The amount of a compound of the invention and/or pharmaceuticalcomposition thereof administered will, of course, be dependent on, amongother factors, the subject being treated, the weight of the subject, theseverity of the affliction, the manner of administration and thejudgment of the prescribing physician.

[0158] For example, the dosage may be delivered in a pharmaceuticalcomposition by a single administration, by multiple applications orcontrolled release. In a preferred embodiment, the compounds of theinvention and/or pharmaceutical compositions thereof are delivered byoral sustained release administration. Preferably, in this embodiment,the compounds of the invention and/or pharmaceutical compositionsthereof are administered twice per day (more preferably, once per day).Dosing may be repeated intermittently, may be provided alone or incombination with other drugs and may continue as long as required foreffective treatment of the disease state or disorder.

[0159] Suitable dosage ranges for oral administration are dependent onthe potency of the parent fused GABA analog, but are generally about0.001 mg to about 200 mg of a compound of the invention per kilogrambody weight. Other fused GABA analogs may be more potent and lower dosesmay be appropriate for both the parent drug and any prodrug (measured onan equivalent molar basis). Dosage ranges may be readily determined bymethods known to the skilled artisan.

[0160] The compounds of the invention are preferably assayed in vitroand in vivo, for the desired therapeutic or prophylactic activity, priorto use in humans. For example, in vitro assays can be used to determinewhether administration of a specific compound of the invention or acombination of compounds of the invention is preferred for reducingconvulsion. The compounds of the invention and/or pharmaceuticalcompositions thereof may also be demonstrated to be effective and safeusing animal model systems.

[0161] Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinvention described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

4.8 Combination Therapy

[0162] In certain embodiments of the present invention, the compounds ofthe invention and/or pharmaceutical compositions thereof can be used incombination therapy with at least one other therapeutic agent. Thecompound of the invention and/or pharmaceutical composition thereof andthe therapeutic agent can act additively or, more preferably,synergistically. In a preferred embodiment, a compound of the inventionand/or a pharmaceutical composition thereof is administered concurrentlywith the administration of another therapeutic agent. In anotherembodiment, a compound of the invention and/or pharmaceuticalcomposition thereof is administered prior or subsequent toadministration of another therapeutic agent.

[0163] Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

[0164] All publications and patents cited herein are incorporated byreference in their entirety.

What is claimed is:
 1. A compound of structural formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein: n is 1, 2, 3, 4, 5 or 6; o is 0, 1, 2 or 3; p is 0, 1or 2; r is 0 or 1; R¹ and R³ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; R² is hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, substituted acyl, acylamino, substitutedacylamino, alkylamino, substituted alkylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, dialkylamino, substituted dialkylamino, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, oxycarbonyl or substitutedoxycarbonyl, or optionally, R² and R³ together with the atoms to whichthey are bonded form a cycloheteroalkyl or substituted cycloheteroalkylring; R⁴ and R⁵ are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, oxycarbonyl or substitutedoxycarbonyl or optionally, R⁴ and R⁵ together with the carbon atom towhich they are bonded form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; R⁶ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; and each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³and R¹⁴ is independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
 2. Thecompound of claim 1, wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ andR¹⁴ is independently hydrogen, alkyl or substituted alkyl.
 3. Thecompound of claim 2, wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ arehydrogen or methyl.
 4. The compound of claim 1, wherein: R¹ is hydrogen,alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl; R² is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkyl or substitutedheteroarylalkanyl or optionally R² and R³ together with the atoms towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; R³ is hydrogen, alkyl, substituted alkyl,arylalkyl or substituted arylalkyl; R⁴ and R⁵ are independentlyhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl or substituted heteroaryl; R⁶ is acyl, substitutedacyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl orsubstituted heteroaryl; and each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ andR¹⁴ is independently hydrogen, alkyl or substituted alkyl.
 5. Thecompound of claim 4, having structural Formula (IV):

wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is independentlyhydrogen or methyl.
 6. The compound of claim 5, wherein the compound isderived from a fused GABA analog selected from the group consisting of:(1α, 3α, 5α)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; and(1α, 3β, 5α)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid.
 7. Thecompound of claim 4 having structural Formula (VIII):


8. The compound of claim 7, wherein the compound is derived from a fusedGABA analog selected from the group consisting of:(6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid; ((1R, 5R,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid; and ((1S, 5S,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid.
 9. The compoundof claim 4, having structural Formula (IX):


10. The compound of any one of claims 4-9, wherein r is 0, R⁴ is methyl,R¹ and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,I-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 11. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is ethyl, R¹ andR⁵ are hydrogen and R⁶ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 12. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is propyl, R¹ andR⁵ are hydrogen and R⁶ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 13. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is isopropyl, R¹and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 14. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is butyl, R¹ andR⁵ are hydrogen and R⁶ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 15. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is isobutyl, R¹and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 16. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is sec-butyl, R¹and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 17. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is cyclopentyl; R¹and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 18. Thecompound of any one of claims 4-9, wherein r is 0, R⁴ is cyclohexyl, R¹and R⁵ are hydrogen and R⁶ is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 19. Thecompound of any one of claims 4-9, wherein r is 0, each of R¹, R⁴ and R⁵is hydrogen, and R⁶ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
 20. Amethod for treating or preventing epilepsy, depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain, inflammatory disease,insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient, comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound according to claim 1.21. A method for treating or preventing neuropathic pain, muscular painor skeletal pain in a patient, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundaccording to claim
 1. 22. A pharmaceutical composition for treating orpreventing epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic,pain, inflammatory disease, insomnia, gastrointestinal disorders orethanol withdrawal syndrome in a patient, comprising a therapeuticallyeffective amount of a compound according to claim 1 and apharmaceutically acceptable vehicle.